1 alpha, 25-Dihydroxyvitamin D3 (calcitriol) is a powerful regulator of calcium metabolism in humans and is used clinically in treating certain calcium metabolic disorders and osteoporosis. Calcitriol has potent anticancer activity and is a candidate for treatment of psoriasis. Some analogs of calcitriol containing an additional fluorine, oxygen, sulfur, or nitrogen atom are likely to be even more useful as medicinal agents than calcitriol itself. In this proposal we describe rational choice and synthesis of several such target calcitriol analogs, including 6- fluorocalcitriol, 2 alpha- and 2 beta-fluorocalcitriol, 2 alpha- hydroxycalcitriol, 1 alpha-mercapto-25-hydroxyvitamin D3, and two amino- hydroxyvitamin D3 compounds. Each of these synthetic drug candidates will be prepared in sufficient quantities for effective biological evaluation (see testing agreement letter at the end of this proposal). The aim of this proposal is also to gain a better chemical understanding of asymmetric inverse-electron-demand Diels-Alder cycloadditions between electron-deficient pyrones and pyridones and electron-rich dienophiles. Toward this goal, a wide variety of dienophiles will be studied on the way to preparing the calcitriol analogs mentioned above. Furthermore, on somewhat more speculative ground, new chemical insights will be sought by examining the following five subjects: (a) intramolecular inverse- electron-demand cycloadditions; (b) more highly electron-deficient pyrones and pyridones; (c) Lewis acid-promoted cycloadditions; (d) heteroatom dienophiles (leading efficiently to asymmetric synthesis of some prosopis piperidine alkaloids); and (e) photochemical transformations of such pyrones and pyridones. Success of this project will produce some important new drug candidates in a very hot area of current world-wide activity (i.e., vitamin D research), and it will also generate significantly enhanced understanding of the chemical limits of a very promising protocol from rapid, efficient, and highly stereocontrolled assembly of various versatile and complex synthetic intermediates.